Studies of the Coagulation System in Arenaviral Hemorrhagic Fever: Experimental Infection of Strain 13 Guinea Pigs with Pichinde Virus

Cosgriff, Thomas M.; Jahrling, Peter B.; Chen, James P.; Hodgson, Loreen A.; Lewis, Richard M.; Green, David E.; Smith, Joseph I.

doi:10.4269/ajtmh.1987.36.416

Cited by 19 publications

(27 citation statements)

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“…In the other rodent models of arenaviral hemorrhagic fever, leukopenia, thrombocytopenia, and a marked depression of a variety of clotting factors have been described. 14,19,20 Some of the Pirital virus-infected hamsters demonstrated hemorrhagic phenomena, such as prolonged bleeding from puncture wounds and bleeding from the mouth at death. In addition, many of the blood samples taken from the infected animals, during the terminal stages of their illness, failed to clot or clotted very slowly.…”

Section: Discussionmentioning

confidence: 99%

“…The Pichinde virus infection model in these two rodent species has many of the virologic, hematologic, and pathologic characteristics of the arenaviral hemorrhagic fevers in humans; and it has been studied by a number of investigators. [15][16][17][18][19][20][21] The purpose of this preliminary report is to describe a new arenaviral hemorrhagic fever model: Pirital virus infection in the Syrian golden hamster. Pirital virus is a newly discovered arenavirus, which was isolated from a cotton rat (Sigmodon alstoni), collected in western Venezuela during epidemiologic studies of Venezuelan hemorrhagic fever.…”

Section: Introductionmentioning

confidence: 99%

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Pirital virus (Arenaviridae) infection in the syrian golden hamster, Mesocricetus auratus: a new animal model for arenaviral hemorrhagic fever.

Xiao¹,

Zhang²,

Yang³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

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Abstract. Adult Syrian golden hamsters inoculated intraperitoneally with Pirital virus, a recently discovered member of the Tacaribe complex of New World arenaviruses, developed a progressively severe, fatal illness with many of the pathologic features observed in fatal human cases of Lassa fever and other arenaviral hemorrhagic fevers. Most of the animals became moribund by Day 5 and were dead by Day 7 after inoculation. The most consistent histopathologic changes included interstitial pneumonitis, splenic lymphoid depletion and necrosis, and multifocal hepatic necrosis without significant inflammatory cell infiltration. The liver changes ranged from single cell death by apoptosis to coagulative necrosis of clusters of hepatocytes. Immunohistochemical studies of the liver demonstrated the presence and accumulation of Pirital virus antigen within hepatocytes as well as Kupffer cells. An in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay showed progressively increasing apoptotic activity in the liver of infected hamsters. A human hepatoblastoma cell line (Hep G2/C3A) inoculated with Pirital virus also developed progressive cell destruction and accumulation of viral antigen, as demonstrated by immunofluorescence. Results of this pilot study suggest that the Pirital virus-hamster model is a very promising new small animal model for studying the pathogenesis of arenavirus infections, particularly, the mechanism of direct virusinduced hepatic injury. It may also be useful for testing antiviral agents for treatment of arenaviral hemorrhagic fevers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pirital virus (Arenaviridae) infection in the syrian golden hamster, Mesocricetus auratus: a new animal model for arenaviral hemorrhagic fever.

Xiao¹,

Zhang²,

Yang³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

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“…The PCV hamster model of acute infection serves as a surrogate model system for identifying potential prophylactic and therapeutic agents that may be efficacious against the more biohazardous arenaviruses. Others have demonstrated that PCV infection of hamsters and guinea pigs provides suitable models for human arenaviral hemorrhagic fever diseases (2,6,9,10,21,33). This study was undertaken to provide insight into the potential use of consensus IFN-␣ for the treatment of acute arenaviral disease.…”

mentioning

confidence: 99%

Interferon Alfacon-1 Protects Hamsters from Lethal Pichinde Virus Infection

Gowen

Barnard

Smee

et al. 2005

Antimicrob Agents Chemother

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Hemorrhagic fever of arenaviral origin is a frequently fatal infectious disease of considerable priority to the biodefense mission. Historically, the treatment of arenaviral infections with alpha interferons has not yielded favorable results. Here we present evidence that interferon alfacon-1, a nonnaturally occurring bioengineered alpha interferon approved for the treatment of chronic hepatitis C, is active against Pichinde and Tacaribe arenaviruses in cell culture. In the hamster model of Pichinde virus (PCV) infection, interferon alfacon-1 treatment significantly protected animals from death, prolonged the survival of those that eventually died, reduced virus titers, and limited liver damage characteristic of PCV-induced disease. Moreover, interferon alfacon-1 also demonstrated therapeutic activity, to a lesser degree, when the initiation of treatment was delayed up to 2 days post-virus challenge. Despite the observed advantages of interferon alfacon-1 therapy, efforts to stimulate the immune system with the known interferon inducer poly(I:C 12 U) (Ampligen) offered only limited protection against lethal PCV challenge. Taken together, these data suggest that the increased potency of the bio-optimized interferon alfacon-1 molecule may be critical to the observed antiviral effects. These data are the first report demonstrating efficacious treatment of acute arenaviral disease with alpha interferon therapy, and further study is warranted.

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“…Serial passage of the Munchique isolate of PIC virus (CoAn 4763) in inbred guinea pigs dramatically increases the pathogenicity of the virus. 2 Guinea pigs infected with this adapted PIC virus develop fever, leukopenia, thrombocytopenia, platelet dysfunction, 3 and terminal vascular collapse 4 in the absence of significant hemorrhagic manifestations, resembling Lassa fever. 5 Like Lassa virus in humans, adapted PIC virus replicates in all extraneural tissues of guinea pigs, and induces minimal histopathologic changes in liver, spleen and other reticuloendothelial organs of the infected host.…”

mentioning

confidence: 99%

Sequence analysis of the small RNA segment of guinea pig-passaged Pichinde virus variants.

Zhang

Marriott

Aronson³

1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. The established animal model for Lassa fever is based on the new world arenavirus Pichinde (PIC). Natural isolates of PIC virus are attenuated in guinea pigs, but serial guinea pig passage renders them extremely virulent in that host. We have compared the nucleotide sequences of the small RNA segments of two attenuated, lowpassage variants of the PIC virus Munchique strain (CoAn 4763) and two virulent, high-passage derivatives. Missense mutations in the glycoprotein precursor (GPC) gene at codons GPC-119, GPC-140, and GPC-164 and the nucleoprotein gene (NP) codons NP-35 and NP-374 were most closely associated with virulence. Codon GPC-140 is predicted to represent a region of peak hydrophilicity of the glycoprotein 1 (GP1); it is conceivable that mutations at this site could influence virulence by altering B cell epitopes or virus attachment protein conformation.Of all the viral hemorrhagic fevers of humans, Lassa fever (caused by the arenavirus Lassa) is most amenable to pathogenesis studies because of the availability of a wellcharacterized, safe, and accurate animal model. This model uses the new world arenavirus Pichinde (PIC), 1 a member of the Tacaribe serogroup, which is non-pathogenic for humans. Serial passage of the Munchique isolate of PIC virus (CoAn 4763) in inbred guinea pigs dramatically increases the pathogenicity of the virus. 2 Guinea pigs infected with this adapted PIC virus develop fever, leukopenia, thrombocytopenia, platelet dysfunction, 3 and terminal vascular collapse 4 in the absence of significant hemorrhagic manifestations, resembling Lassa fever. 5 Like Lassa virus in humans, adapted PIC virus replicates in all extraneural tissues of guinea pigs, and induces minimal histopathologic changes in liver, spleen and other reticuloendothelial organs of the infected host. [6][7][8] In contrast, the parental, unpassaged virus is naturally attenuated, and causes a self-limited febrile illness with low mortality in inbred guinea pigs. 2 This system offers the opportunity to delineate molecular genetic determinants of virulence. The relatively short passage history of parent (attenuated) and passaged (virulent) PIC virus suggests that sequence analysis would uncover a relatively small number of mutations between the two; the disparate virulence phenotypes favors the correlation of pathogenicity with specific viral genetic alterations.Arenaviruses have bipartite, ambisense, single-stranded RNA genomes. The small (S) segment encodes the viral envelope glycoproteins and nucleoprotein. 9 The glycoprotein precursor (GPC) protein is translated from a virus sense mRNA derived from the 5Ј half of the S segment. The GPC polypeptide is post-translationally processed by host cell signal peptidase and furin-like proteases to yield GP1 and GP2. Biochemical studies suggest that tetramers of GP2, which have a transmembrane domain, form a coiled-coil stalk, atop which tetramers of the globular GP1 protein are bound by non-covalent interactions.9,10 The cytoplasmic tails of the GP2 molecules are believe...

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Studies of the Coagulation System in Arenaviral Hemorrhagic Fever: Experimental Infection of Strain 13 Guinea Pigs with Pichinde Virus

Cited by 19 publications

References 0 publications

Pirital virus (Arenaviridae) infection in the syrian golden hamster, Mesocricetus auratus: a new animal model for arenaviral hemorrhagic fever.

Pirital virus (Arenaviridae) infection in the syrian golden hamster, Mesocricetus auratus: a new animal model for arenaviral hemorrhagic fever.

Interferon Alfacon-1 Protects Hamsters from Lethal Pichinde Virus Infection

Sequence analysis of the small RNA segment of guinea pig-passaged Pichinde virus variants.

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